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    Home > Active Ingredient News > Blood System > CPX-351 can significantly prolong OS in newly diagnosed high-risk/secondary elderly AML patients: post-mortem analysis of phase 3 study

    CPX-351 can significantly prolong OS in newly diagnosed high-risk/secondary elderly AML patients: post-mortem analysis of phase 3 study

    • Last Update: 2021-05-10
    • Source: Internet
    • Author: User
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    CPX-351 (liposomalized daunorubicin/cytarabine [5:1] complex) has been approved by the U.
    S.
    Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for new use Diagnose and treat adult patients with related acute myeloid leukemia (t-AML) or AML (MRC-AML) associated with myelodysplastic changes.

    The preliminary results of a key, randomized phase 3 study of newly diagnosed high-risk/secondary elderly AML patients showed that CPX-351 was used for consolidation therapy after induction therapy, and the median overall survival (OS [primary endpoint]; 9.
    56 vs 5.
    95 Month; HR: 0.
    69; 95% CI: 0.
    52-0.
    90; unilateral P=0.
    003) significantly improved, and compared with the 7+3 regimen, CPX-351 complete remission / complete remission with incomplete blood count recovery ( The CR/CRi) rate was significantly higher (48% vs 33%; bilateral P=0.
    016).
    In addition, the safety of CPX-351 was consistent with the known safety of the 7+3 regimen.

    Traditional chemotherapy methods have poor durability in remissions in patients with secondary AML.

    A large-scale registration study has confirmed the above view.
    The study found that compared with newly diagnosed AML patients, patients with previous hematological diseases or t-AML who achieved CR through conventional chemotherapy have significantly reduced OS from the time they reached CR, and compared with newly diagnosed AML patients.
    Cytogenetic risk is irrelevant.

    Therefore, the researchers conducted a post-event exploratory subgroup analysis of the key phase 3 study of CPX-351 to explore the remission of CPX-351 compared with the conventional 7+3 regimen on the survival, survival, and survival of high-risk/secondary elderly AML patients.
    The impact of hematopoietic cell transplantation (HCT) and safety prognosis.

    Research Method The study is an open, controlled, multi-center, phase 3 clinical study.
    Patients were randomly assigned to receive CPX-351 or 7+3 induction therapy at a ratio of 1:1.

    Received CPX-351 100 units/m2 (daunorubicin 44mg/m2 + cytarabine 100mg/m2 on day 1, day 3, and day 5 (the second induction is day 1 and day 3) Accept up to 2 cycles of induction therapy) infusion for 90 minutes, or 7+3 regimen (continuous infusion for 7 days [the second induction is 5 days] cytarabine 100mg/m2 + day 1, 2 and 3 [second The second induction is the first day and the second day] infusion of daunorubicin 60mg/m2).

    The researchers recommend a second induction for patients who have demonstrated a reduction in leukemia burden, and for patients whose blast count drops by more than 50% on the 14th day, a second induction is necessary.

    Patients who achieve CR/CRi can receive up to 2 cycles of 65 units/m2 CPX-351 (daunorubicin 29mg/m2 + cytarabine 65mg/m2, infusion for 90 minutes on day 1 and day 3) or 5+2 program (100mg/m2 cytarabine continuous infusion for 5 days + 60mg/m2 daunorubicin infusion on day 1 and day 2) consolidation therapy.

    Patients can receive HCT according to the doctor's discretion.

    The primary study endpoint is OS, and the secondary study endpoints include remission rate (CR, CR+CRi) and duration of remission.

    The proportion of patients receiving HCT was also evaluated.

    Study Results 01 Patient Characteristics A total of 309 patients were randomly assigned to CPX-351 group (n=153) or 7+3 group (n=156).

    In CPX-351 group and 7+3 group, 73 cases (48%) and 52 cases (33%) obtained CR+CRi (OR: 1.
    77; 95% CI: 1.
    11-2.
    81), respectively, 57 cases (37%) And 40 cases (26%) obtained CR (OR: 1.
    69; 95% CI: 1.
    03-2.
    78).

    Compared with the 7+3 group, the t-AML subgroup (47% vs 36%) and the AML-MRC subgroup (48% vs 33%) in the CPX-351 group had a higher incidence of CR+CRi.

    Among patients who received only one cycle of induction therapy, the CR+CRi rates of CPX-351 group and 7+3 group were 55% (58/105) and 34% (34/100), respectively, and the CR rate was 45% ( 47/105) and 28% (28/100).

    For patients who received 2 cycles of induction therapy, the CR+CRi rates of the CPX-351 group and 7+3 group were 31% (15/48) and 35% (18/51), respectively, and the CR rate was 21% (10 /48) and 24% (12/51).

    In the multivariate analysis, the karyotype (favorable/moderate vs unfavorable; OR: 3.
    95; 95% CI: 2.
    12-7.
    37; P<0.
    001), white blood cell count (<20×103/µL vs ≥20×103/µL; OR: 3.
    48; 95% CI: 1.
    47-8.
    22; P=0.
    005) and treatment group (CPX-351 vs 7+3; OR: 1.
    85; 95% CI: 1.
    12-3.
    08; P=0.
    017) are related to achieving CR/CRi .

    In addition, although karyotype, gender, white blood cell count, and treatment group are related to CR, only karyotype is related to CRi.

    Between the CPX-351 and 7+3 treatment groups, all patients who achieved CR, CRi, and CR/CRi had similar baseline characteristics.

    02 Duration of remission For all CR/CRi patients, the median duration of remission for the CPX-351 group and 7+3 group were 6.
    93 months and 6.
    11 months, respectively (HR: 0.
    77; 95% CI: 0.
    47-1.
    26); In patients with CR, the median time to remission was 7.
    89 months vs.
    6.
    54 months (HR: 0.
    90; 95% CI: 0.
    54-1.
    49); in patients with CRi, the median time to remission was 5.
    32 months vs.
    3.
    09 Months (HR: 0.
    46; 95% CI: 0.
    17-1.
    20).

    03OS reached CR/CRi (25.
    43 months vs 10.
    41 months HR: 0.
    49; 95% CI: 0.
    31-0.
    77), CR (25.
    43 months [n=57] vs 10.
    97 months [n=40]; HR: 0.
    49 ; 95% CI: 0.
    29-0.
    83) and CRi (13.
    70 months [n=16] vs 8.
    97 months [n=12]; HR: 0.
    48; 95% CI: 0.
    19-1.
    26) compared to 7 The median OS of patients in the +3 group was longer in the CPX-351 group.

    In multivariate analysis, the karyotype of CR/CRi patients (favorable/moderate vs unfavorable; HR: 0.
    48; 95% CI: 0.
    30-0.
    79; P=0.
    003), platelet count (≤50×103/µL vs> 50×103/µL; HR: 1.
    83; 95%CI: 1.
    11-3.
    01; P=0.
    017) and treatment group (CPX-351 vs 7+3; HR: 0.
    40; 95%CI: 0.
    25-0.
    65; P<0.
    001) Related to OS.

    In addition, in the subgroup of patients with t-AML, AML-MRC, 60-69 years old, 70-75 years old who reached CR/CRi, compared with the 7+3 regimen, the median OS treated with CPX-351 was longer.
    In t-AML (not reached vs 9.
    15 months; HR: 0.
    21; 95% CI: 0.
    07-0.
    68) and 70-75 years of age (25.
    43 vs 8.
    41 months; HR: 0.
    30; 95% CI: 0.
    13-0.
    65) subgroups The most significant improvement in OS was observed in patients.

    It should be noted that there are fewer patients in certain subgroups.

    04HCT status 52 patients in CPX-351 group (34%) and 39 patients in 7+3 group (25%) received HCT.

    Among the patients with CR/CRi, the CPX-351 group had a higher HCT rate compared with the 7+3 group (40/73[55%] vs 24/52[46%]; OR: 0.
    71; 95% CI: 0.
    35-1.
    44).

    Among the patients who achieved CR, the HCT rates of the CPX-351 group and 7+3 group were 53% (30/57) and 48% (19/40), respectively.
    Among the patients who achieved CRi, it was 63% (10/16).
    ) And 42% (5/12).

    And compared with the 7+3 group, the median OS (from the date of transplantation) of patients who used CPX-351 to achieve CR/CRi was longer (not reached vs 11.
    65 months; HR: 0.
    43; 95% CI: 0.
    21- 0.
    89).

    05 Safety The safety of CPX-351 in patients with CR/CRi is consistent with the known safety of the overall study population and the 7+3 regimen.

    Among patients who achieved CR/CRi, the most common Grade 3-5 treatment emergency (TEAE; ≥10%) during the study period was febrile neutropenia (CPX-351: 79% vs 7+3: 77 %), hypertension (14% vs 6%), pneumonia (12% vs 15%), bacteremia (11% vs 2%), sepsis (6% vs 10%) and pulmonary edema (3% vs 10% ).

    Febrile neutropenia (CPX-351: 15% vs 7+3: 12%) is the most common serious TEAE.

    One patient in the CPX-351 group was discontinued due to TEAE (heart failure).

    Research Conclusions This large, multi-center, randomized controlled phase 3 clinical study shows that, compared with the traditional 7+3 regimen, CPX-351 can achieve deeper remission in high-risk/secondary elderly AML patients, thereby improving OS.
    And the security is equivalent.

    Reference source: Tara L.
    Lin, David A.
    Rizzieri, Daniel H.
    Ryan, et al.
    Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses.
    Blood Adv (2021 ) 5 (6): 1719–1728.
    https://doi.
    org/10.
    1182/bloodadvances.
    2020003510.
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